DESCRIPTION (the applicant's description verbatim): Aortic aneurysm is an often fatal cardiovascular disease. Many aortic aneurysms are clinically silent until they rupture with devastating clinical consequences. At least 20 percent of aortic aneurysms result from hereditary mendelian disorders. Although monogenic autosomal dominant familial aortic aneurysm (FAA) can occur as one feature of Marfan and Ehlers-Danlos Type IV syndromes, most individuals with FAA do not satisfy diagnostic criteria for these connective tissue disorders, and the existence of unrelated FAA genes and mutations has long been hypothesized. To date, however, no other gene defect has been identified. In this project, we will identify FAA gene(s) responsible for aortic aneurysm formation. We have used echocardiographic techniques to identify 7 families who are affected by autosomal dominant FAA without clinical findings of extracardiovascular connective tissue disease. Linkage analysis of family ANB reveals that FAA, in this kindred, results from a fibrillin-1 gene locus defect and is a fibrillinopathy. However, linkage analysis demonstrates that FAA in another kindred (ANA) is not linked to the fibrillin-1, fibrillin-2, or the type III procollagen genes. Therefore, aortic aneurysms in family ANA do not represent a forme fruste of Marfan or Ehlers-Danlos syndromes. Kindred size, autosomal dominant inheritance, and the high degree of penetrance make FAA in ANA and other identified families particularly suitable for molecular genetic analysis. We therefore propose: (1) To identify the chromosomal location of the gene responsible for monogenic FAA in family ANA, (2) To characterize the extent of FAA genetic heterogeneity by defining the location of the mutated gene(s) segregating in other families, (3) To refine genetic and physical maps of each FAA locus and identify candidate genes, (4) To identify genes with mutations that cause FAA, and (5) To assess the role of the FAA gene in causing nonfamilial aortic aneurysms. Genome wide linkage analysis is currently underway to establish the chromosomal location of the genes responsible for FAA in family ANA and other families. Once FAA loci are identified, we will study several large and small families to determine the relative contributions of FAA loci to aortic aneurysm formation in these populations. We will then employ positional cloning technology to identify the specific gene defect(s) at FAA chromosomal loci. Mutational analysis of these genes in individuals with sporadic aortic aneurysms will define their contribution to the genesis of common nonfamilial aortic aneurysms. We anticipate that the identification of novel genes which contribute to vascular wall instability and aneurysm formation will enhance our ability to make preclinical diagnoses in individuals at risk. Moreover, characterization of these genes will provide a platform for the development of experimental models of cardiovascular disease and to develop innovative pharmacologic strategies to prevent or to retard aortic aneurysm formation.